1-(tertiary-aminoalkylamino) acridones and their method of preparation



Patented Aug. 4, 1953 1- (TERTIARY-AMINOALKYLAMINO) ACRIDONES AND THEIR METHOD" OF PREPARATION Sydney Archer, Albany, N. Y., assignor to Sterling Drug Inc., New York, N. Y., a. corporation of Delaware No Drawing.

Application May 6, 1952,

Serial No. 286,427

22 Claims. 1

This invention relates to l-(tertiary-aminoalkylamino)acridones and to their method of preparation. In particular, it relates to such acridones having the structure where X is CHzCHOI-ICHz or a lower alkylene radical, NRiRz is a tertiary-amino radical, and R3, R4 and R are each hydrogen, a lower alkyl radical or a halo radical.

These compounds of my invention are useful because of their dyeing and tinting properties, the compounds being from yellow to orange in color. The compounds also have useful pharmaceutical properties, for instance, bacteriostatic and bactericidal properties.

In the above structure, X when a lower alkylene radical has its two connecting linkages on different carbon atoms, so therefore X must contain at least two carbon atoms. X contains preferably not more than six carbon atoms. Thus, X when lower alkylene includes such radicals as and the like. The tertiary-amino radical shown above as NR1R2 comprehends dialkylamino radicals where R1 and R2 are each lower alkyl radicals, alike or difierent, and each alkyl radical having preferably from one to six carbon atoms inclusive, such dialkylamino radicals including dimethylamino, methyl-ethylamino, diethylamino, diisopropylamino, ethyl n propylamino, di-nbutylamino, di-n-hexylamino, and the like. Also, the tertiary-amino radical designated as NRIRZ encompasses saturated N -heteromonocyclic radicals having five to siX ring atoms, illustrated by examples such as l-piperidyl; (lower alkylated)-1- piperidyl such as 2-methyl-1-piperidyl, 3-ethyl-l-piperidyl, 4-methyl-1-piperidyl, 2,6-dimethyl-l-piperidyl; l-pyrrolidyl; (lower alkylated) -1-pyrrolidyl such as 2-methyl-1-pyrro1idyl, 2,5-dimethyl-l-pyrrolidyl; 4-morpholinyl; and

the like. R3, R4 or R5 when a. halo radical'means chloro, bromo, iodo and fluorot- R3, R4 or R5 when a lower alkyl radical has preferably one to six carbon atoms inclusive, including such radicals as methyl, ethyl, n-propyl, isopropyl, n-butyl,.

HzNX NR1R2 with a. l-haloacridonehaving the formula where halogen means chloro, bromo, iodo and fluoro, and where R3. R4. and R5 have the meanings given hereinabove. Illustrations of this process and the resulting compounds of my invention are asfollows: I-(Z-diethylaminoethylamino) -4-ethyl-6-bromoacridone from Z-diethylaminoethylamine and 1,6-dibromo-4-ethylacridone l- (3-dimethylamino-2-propylamino) -4nhexylacridone from 3-dimethylamino-2-propylamine and 1-chloro-4-n-hexylacridone; 1-(5-diethylamino 2 pentylamino) 3,4,6 trimethylacridone from 5-diethylamino-2-pentylamine and I-chloro-3,4,6-trimethylacridone; l (3-diethylamino2-2-hydroxypropylamino) -4 methyl 6-' chloroacridone from 3-diethylamino-Z-hydroxypropylamine and 1,6-dichloro-4-methy1acridone; 1-(2-di n butylaminoethylamino) 3,4,6 tri-, chloroacridone from 2-di-n-butylamineoethylamine and l,3,4,6-tetrachloroacridone; 1-[3-(1- piperdyl) propylamine] -3-bromoacridone from 3- (l-piperidyhpropylaminc and 1,3-dibromoacridone; 1- [2- (2-methyl-1-piperidyl) ethylamino] 4-n-propyl-6-iodoacridone from 2-(2-Tmethyl-lpiperidyDethylamine and l,6-diiodo-4-n-propylacridone; 1 L3 (l-pyrrolidyl) -propylamino]-4- methyl-S-n-butylacridone from 3-(1-pyrrolidyl) propylamine and l-chloro-4-methyl-S-n-butylacridone; 1 [2 2,5 dimethyl-l-pyrroolidyl) ethylamino] 3 isobutylacridone from 2 (2,5- dimethyl-l-pyrrolidyl)ethylamine and l-chloro- 3-isobutylacridone; l [z-(l-morpholinyl)ethylamino] -4-methyl-6 fiuoroacridone from 2-(4- morpholinyl) ethylamine and 1,6-difluoro 4- methylacridone.

The intermediate l-haloacridones are generally known, as are their methods of preparation.

For example, a useful method is the cyclization of an ortho-(meta-halophenylamino)benzoic acid, preferably done by heating the benzonic acid derivative in the presence of a strong mineral acid, e. g., concentrated sulfuric acid. The ortho-substituted-benzoic acid is readily obtained by heating a metal salt, preferaby an alkali metal salt, of an ortho-halobenzoic acid with a meta-haloaniline in the presence of a copper powder catalyst. This method is illustrated by the preparation of 1-chloro-4-ethyl-fi-bromoacridone by first heating potassium 2,4-dibromobenzoate with 2- ethyl--chloroaniline in the presence of copper powder to form potassium 2-(2-ethyl-5-chlorophenylamino) -4-bromobenzoate, which is isolated in the form of its acid, and then heating this substituted-benzoic acid with concentrated sulfuric acid to form the 1-ch1oro-4-ethyl-6-bromoacridone. Another illustration is the formation of 1-brom0-3,4-dimethyl-6-chloroacridone by first preparing 2 (2,3 dimethyl 5 -bromophenylamino) -4-chlorobenzoic acid from potassium 2,4- dichlorobenzoate and 2,3 dimethyl 5-bromoaniline and then cyclizing said phenylaminochlorobenzoic acid.

My 1 (tertiary aminoalkylamino) acridones can be isolated either in the form of the free bases or in the form of their salts with relatively nontoxic organic or inorganic acids, and can be used in either form. In practicing my invention I have found it convenient to isolate my acridones in the form of their acid addition salts, especially the hydrochloridesj however, other acid addition salts are within the scope of my invention, such salts including the hydrobromides, hydroiodides, phosphates, sulfates, citrates, ethanesulfonates, tartrates, succinates, acetates, benzoates, mandelates, oleates, and the he.

My invention also comprehends quaternary ammonium salts of the above defined 1- (tertiaryaminoalkylamino)acridones, said salts being derived from alkyl or benzyl esters of an acid, either inorganic or organic. Such esters include methyl iodide, methyl bromide, ethyl chloride, ethyl bromide, ethyl sulfate, n-propyl iodide, isobutyl bromide, n-hexyl iodide, n-dodecyl chloride, benzyl chloride, methyl para-toluenesulfonate, ethyl para-toluenesulfonate, ethyl benzenesulfonate, and the like, the respective quaternary salts being the methiodides, methobromides, ethochlorides, ethobromides, ethosulfates, n-propiodides, isobutobromides, n-hexiodides, n-dodecochlorides, benzochlorides, metho-para-toluenesulfonates, etho-paratoluenesulfcnates, ethobenzenesulfonates, and the like.

Specific embodiments of my invention are further illustrated in the following examples.

EXAMPLE 1 1- (3-diethylaminopropylamino) 4-chloroacridone A mixture of g. of 1,4-dichloroacridone and 25 g. of S-diethylaminopropylamine was refluxed for four hours. The mixture was then steam distilled and the residue made basic. The basic mixture was allowed to settle and the supernatant liquor decanted through a filter aid. The filter aid and gummy residue were washed with water and then treated with a boiling 5% aqueous hydrogen chloride solution. The acidic solution was filtered and taken to dryness. The residual material was covered with ethanol and taken to dryness again; this procedure was repeated with ethanol and then once with toluene. The residue crystallized. The crystalline residue was boiled with absolute ethanol and to the boiling mixture was added about 10 ml. of ethanolic hydrogen chloride whereupon dissolution was effected. The hot solution was treated with decolorizing charcoal, filtered and the filtrate was treated with two volumes of ether. On cooling, crystals separated. A sec-0nd recrystallization of this crystalline product from ethanol-ether, the ethanol containing a few ml. of ethanolic HCl, yielded as yellow-green plates the product, l-(3-diethylaminopropylamino) -4-chloroacridone in the form of its hydrochloride salt. A sample of this product melted at 238.5-239.5 C. (cor.) when recrystallized once more from ethanol and dried at 1 mm. over concentrated sulfuric acid.

Anal.Calcd. for C2oH24C1N30.HClZ N, 10.66; Cl, 17.98. Found: H2O, 0.8; N, 10.38 (dry basis); 01, 17.80 (dry basis).

1 (3 diethylaminopropylamino) 4 chloroacridone hydrochloride had bacteriostatic and bactericidal activity against the following organisms: Streptococcus pyogenes, Eberthella typhosa, Brucella abortus, Mycobacterium tuberculosis and Clostridium welchii.

1 (3 diethylaminopropylamino) 4 chloro acridone in free base form is obtained by treating an aqueous solution of its hydrochloride with alkali, e. g., 40% aqueous sodium hydroxide solution, extracting the product thereby liberated with chloroform and removing the chloroform by distilling in vacuo.

l (3 diethylaminopropylamino) 4 chloroacridone in the form of a quaternary salt derivative is formed by treating the free base form of this compound with the appropriate alkyl or benzyl ester of an organic or inorganic acid. For example, its treatment, in ethanolic solution, with methyl iodide, ethyl sulfate, n-dodecyl chloride, benzyl chloride or ethyl para-toluenesulfonate results in the formation of 1-(3-diethylaminopropylamino)-4-chloroacridone methiodide, 1- (3 diethylaminopropylamino) 4 chloroacridone ethosulfate, 1 (3 diethy1aminopropylamino) -4-chloroacridone n-dodecochloride, 1-(3- diethylaminopropylamino) 4 chloroacridone benzochloride or 1 (3 diethylaminopropylamino) -4-chloroacridone etho-para-toluenesulfonate, respectively.

Other 1 (tertiary aminoalkylamino) 4- haloacridones, in the form of their free bases, acid addition salts or quaternary ammonium salts, can be prepared according to the procedures given above but using other 1,4-dihaloacridones and tertiary-aminoalkylamines in place of 1,4- dichloroacridone and 3 diethylaminopropylamine, respectively. Thus, 1-[3-(1-piperidyl) propylaminol-4-chloroacridone is obtained from 1,4-dichloroacridone and 3(1-piperidyl)propylamine; 1 (3 diethylamino 2 propylamino) 4-bromoacridone, from l,4-dibromoacridone and 1diethylamino-2propylamine (same as 3-diethylamino-2-propylamine) 1-[3- (2-methyl-1- piperidyl) propylamino] -4-chloroacridone, from 1,4-dichloroacridone and 3-(2-methyl-1-piperidyl)propylamine; l [4 (1 pyrrolidyDbutylaminol-4-iodoacridone, from 1,4-diiodoacridone and 4 (1 pyrrolidyDbutylamine; 1 [3 (2,5- dimethyl 1 pyrrolidyl)propylamino] 4 chloroacridone, from 1,4-dichloroacridone and 3- (2,5-dimethyl-l pyrrolidyl) -propylamine; 1- [2- (4 morpholinyDethylamino] 4 fluoroacridone, from 1,4-difluoroacridone and 2-(4-morpholinyDethylamine; 1 (2 diethylaminoethylamino) -3methyl4-chloroacridone, from 1,4-dichloro-B-methylacridone and 2-diethylamino- 5 ethylamine; 1 [3- CI-piperidyl) propylaminol -3- n-propyl-4-bromoacridone, from 1,4-dibromo-3- n-propylacridone and 3-('1-piperidyl)-propy1- amine; I (2 diethylaminoethylamino) 3,6- diethyl-4-chloroacridone, from lA-di'chloro-lifidiethylacridone and.Z-diethylaminoethylamine.

EXAMPLE 2 1 5 -di thyZamin-2-pentylamino) -chloroac'rtdone A. mixture of 10 g. of 1,4-dichloroacridone and 34 g. of -diethylamino-2-pentylamine was re fluxed for two hours. The mixture was then made basic with 40% aqueous sodium hydroxide solution and steam distilled. The gummy residual material was taken up with 200 ml. of aqueous acetic acid solution. This acidic solution was filtered an dthe filtrate'made basic and cooled. The precipitated product was dissolved in ethanol and the resulting solution concentrated to dryness in vacuo. The residue was covered with toluene and taken to dryness again. The residue was then dissolved in ethanoland the ethanolic solution treated with ethanolic hydrogen chloride, followed by the addition of ether. The solid that separated was collected and recrystallized from absolute ethanol, with charcoaling, yielding as yellow prisms, l-(5-diethylamino-2-pentylamino) -4chloroacridone in the form of its hydrochloride, melting at 245-246.6 C. (cor.) when dried for forty-eight hours at 90 C.

Anal.--Calcd. for C22H2sC1N3QHC1: C, 62.55; H, 6.92; N, 9.97; Cl, 16.82. Found: C, 62.45; 15.6.94; N, 9.67; Cl, 16.62.

The above product had bacteriostatic and bactericidal activity against the following organisms: Streptococcus pyogenes, Eberthella typhosa, Brucella abortus, Mycobacteriwm tuberculosz's and Clostrz'dium weZc-hii.

1 (5 diethylamino 2 pentylamino) -4 chloroacridone in the form of its free base is obtained by treating an aqueous solution of its hydrochloride with alkali, extracting the product thereby liberated with chloroform and removing the chloroform by distilling in vacuo.

Following the above procedure but using 1,4- dibromoacridone, 1,4-diiodoacridone or 1,4-difluoroacridone in place of 1,4-dichloroacridone,

A. 1,3-dz'chtoroacridone A mixture of 45 g. of potassium Z-bromobenzoate, g. of 3,5-dichloroaniline, 100 g. of n-amyl alcohol and 1 g. of copper powder was refluxed with stirring for four hours. The reaction mixture was then steam distilled after the addition of a few ml. of aqueous potassium hydroxide solution. The residual material was filtered off and the filtrate was acidified, thereby precipitating a solid that was collected. The solid was recrystallized from acetic acid, adding enough water to the hot acetic acid to effect dissolution. There was thus obtained 28 g. of 2-(3,5dichlorophenylamino)benzoic acid of sufiicient purity to be used in the following reaction. A sample of this intermediate acid was recrystallized as above.

and submitted for analysis, M. P. 240442. c.

Anal-Calcd. for CisHsClzNOc: N, 4.94; CI, 25.13. FoundfN, 4.90; 01,2434.

A mixture of 26 g. of 2- (3,5-dichlorophenylamino)benzoic acid and ml. of concentrated sulfuric acid was stirred on a steam bath for one hour, poured into water and the product collected. The product was suspended in dilute aqueous sodium hydroxide solution, steam passed through the mixture for about thirty minutes and the solid filtered and dried. This product, 1,3-dichloroacridone, Weighed about 22 g. and was used in the procedure described below as Example 33. A sample of this product was recrystallized from pyridine for analysis, M. P. 250 C.

Anal.Calcd. for CiaHqClzNO: Cl, 26.81; N, 5.3. Found; Cl, 26.48; N, 5.0.

Other 1,3-dihaloacridones can be prepared according to the procedure given above but using other potassium 2-halobenzoates and 3,5-dihaloanilines in place of potassium 2-bromobenzoate and 3,5-dichloroaniline, respectively. Thus, 1,3-dibromoacridone is obtained from potassium 2,-bromobenzoate and 3,5-dibromoaniline; 1,3-diiodoacridone, from potassium 2-bromobenzoate and 3,5-diiodoaniline; 1,3-difluoroacridone, from potassium 2,-bromobenzoate and 3,5-difluoroaniline; l',3'-dichloro-4-methylacridone, frompotassium 2-bromobenzoate and 2-methyl3,5-dichloroaniline; 1,3-dichloro-4-methy1-6-ethylacridone, from potassium 2-bromo-4-ethylbenzoate and 2-methyl-3,5-dichloroaniline; 1,3-dibromo-G-n-hexylacridone, from potassium Z-bromo- 4-n-hexylbenzoate and 3,5-dibromoaniline.

B. 1 (3 diethytaminopr pytamino) 3-chloroacrtdone A mixture of 15 g. of 1,3-dichloroacridone and 50 g. of 3-diethylaminopropylamine was refluxed for four hours. The mixture was poured into water and the solution treated with hydrogen chloride. Addition of ethanol was necessary to efiectcomplete dissolution of the product. The solution was then filtered and the filtrate made basic and cooled. The solid was collected and recrystallized twice from ethanol-water, using decolorizing charcoal the second time. The solid was then dissolved inabsolute ethanol andethanolic hydrogen chloride added. The precipitated product, 1-(8-diethylaminopropylamino) B-chloroacridone in the form of its hydrochloride, melted at 269.8-270.8 C. cor.) when dried at 65 C. overnight.

Anal.-Calcd. for C20H24C1N30.HC1: N, 10.66; Cl,'-17.98. Found: E20, 1.54; N, 10.57 (dry basis) C1. 17.88 (dry basis).

The above product had bacteriostatic and bactericidal activity against the following organisms: Streptococcus pyogenes, Eberthella typhosa, Brucella abortus, Mycobacterium tuberculosis and C'Zostrz'dium welchii.

l (3 diethylaminopropylamino)-3-chloroacridone in the form of its free base is obtained by treating an aqueous solution of its hydrochloride with 40% aqueous sodium hydroxide solution, extracting the product that separates 7 aminol-3-iodoacridone or 1-(3-diethylaminopropylamino) -3-fiuoroacridone, respectively.

Other 1- (tertiary-aminoalkylamino) -3-haloacridones, in the form of their free bases or acid addition salts, can be prepared according to the procedure given above, but using other 1,3-dihaloacridones and tertiary-aminoalkylamines in place of 1,3-dichloroacridone and 3-diethylaminopropylamine, respectively. Thus, 1-[3- (l-piperidyl) propylamino] -3-chlo'roacridone is obtained from 1,3-dichloroacridone and 3-(1- piperidyDpropylamine; 1 (5-diethylamino-2- pentylamino)3-bromoacridone, from 1,3-dibromoacridone and 5-diethylamino-2-pentylamine; 1 [3-(2 methyl-l-piperidyl)propylamino]-3-chloroacridone, from 1,3-dichloroacridone and 3-(2-methyl-1-piperidyl)propylamine; 1 [4 (l-pyrrolidyl)butylaminol-S- iodoacridone, from 1,3-diiodoacridone and 4- (l-pyrrolidyl) butylarnine; 1- [3--(2,5-dimethyl- 1 pyrrolidyl)propylamino]-3-chloroacridone, from 1,3-dichloroacridone and 3-(2,5-dimethyl- 1 pyrrolidybpropylamine; l [2-(4-morpholinyl)ethylamino]-3-fiuoroacridone, from 1,3- difiuoroacridone and 2-(4-morpho1inyl)ethylamine; 1-(2-diethylaminoethylamino)-3-chloro-4-methylacridone, from 1,3-dichloro-4-methylacridone and 2-diethylaminoethylamine; 1-[3- (1 piperidyDpropylaminol 3 bromo-4-npropylacridone, from 1,3-dibromo-4-n-propylacridone and 3-(1-piperidyl)-propylamine; 1- (2 diethylaminoethylamino) 3 chloro 4- methyl-G-ethylacridone, from 1,3-dichloro-4- methyl-S-ethylacridone and 2-diethylaminoethylamine; 1 [2-(1-piperidyl)ethylamino]-3- bromo-S-n-hexylacridone, from 1,3-dibromo-6- n-hexylacridone and 2-(1-piperidyl) ethylamine.

EXAMPLE 4 A. 1,4,6-trichloroacridone The intermediate 2-(2,5-dichlorophenylamino)-4-chlorobenzoic acid was prepared following the procedure described above for Example 3A, but using 21 g. of potassium 2,4-dichlorobenzoate, 16 g. of 2,5-dichloroaniline, 50 ml. of n-amyl alcohol and 1 g. of copper powder. This intermediate acid was obtained as light yellow needles, M. P. 262-264 C. when dried at 100 C.

Anal.Calcd. for CrsHsClzNOzI N, 4.43; Cl, 33.60. Found: N, 4.30; Cl, 35.10.

1Afl-Trichloroacridone was then obtained following the procedure described above in Example 3A but using 6 g. of 2-(2,5-dichlorophenylamino)-4-chlorobenzoic acid, 80 g. of concentrated sulfuric acid and a heating period of onehalf hour on a steam bath. The product, 1,4,6- trichloroacridone, weighed 4.3 g. after one recrystallization from acetic acid and drying at 100 C. for twenty-four hours; M. P. 242-243 C.

Anal.--Calcd. for C13H6C13NOZ N, 4.68; Cl, 35.63. Found: N, 4.56; Cl, 35.55.

Other 1,4,6-trihaloacridnes can be prepared according to the procedure given above but using other potassium 2,4-dihalobenzoates and 2,5-dihaloanilines in place of potassium 2,4-dichlorobenzoate and 2,5-dichloroaniline, respectively. Thus, 1,4,6-tribromoacridone is obtained from potassium 2,4-dibromobenzoate and 2,5-dibroinoaniline; 1,4,6-triiod0acridone, from potassium 2 bromo 4 iodobenzoate and 2,5-diiodoaniline; 1,4,6-trifluoroacridone, from potassium 2-bromo-4-fluorobenzoate and 2,5-dii1uoroaniline; 1,4,6 trichloro 3 methylacridone, from potassium 2,4-dichlorobenzoate and 2,5- dichloro 3 methylaniline; 1.4,6-tr1ch1oro-3- ethylacridone, from potassium 2,4-dichloroben zoate and 2,5-dichloro-3-ethylaniline; 1,4,6- tribromo-3-n-hexylacridone, from potassium 2,4 dibromobenzoate and 2,5 dibromo-S-nhexylaniline.

B. 1- (3-diethylaminopropulamino) -4,6-

dichloroacridone A mixture of 12 g. of 1,4,6-trichloroacridone and 32 g. of 3-diethylaminopropylamine was refluxed for three hours. The mixture was poured into water, and the solution was treated with hydrochloric acid and cooled. The precipitate that separated was collected and recrystallized several times from absolute ethanol. There was thus obtained as yellow prisms, 7.7 g. of 1-(3- diethylaminopropylamino) 4,6 dichloroacridone as its hydrochloride, M. P. 256-258 C. (cor.) when dried at C. for ninety-six hours.

Anal.Calcd. for C2oH22C12N3O.HC1I N, 9.85; 24.93. Found: N, 9.75; Cl, 24.69.

The above product had bacteriostatic and bactericidal activity against the following organisms: Streptococcus pyogenes, Ebertheila typhosa, Brucella abortus, Mycobacterium tuberculosis and Clostridz'um welchii.

Other 1 (tertiary aminoalkylamino) 4,6- dihaloacridones, in the form of their free bases or salts, can be prepared according to the procedure given above, but using other 1,4,6-trihaloacridones and tertiary-aminoalkylamines in place of 1,4,6-trichloroacridone and 3-diethylaminopropylamine, respectively. Thus, 1-[3-(1- piperidybpropylaminol 4,6 dichloroacridone is obtained from 1,4,6-trichloroacridone and 3-(1- piperidyl)propylamine; 1 (5 diethylamino 2- pentylamino)-4,6-dibromoacridone, from 1,4,6- tribromoacridone and -5-diethylamino-2-pentylamine; 1- [3- (2-methyl-1-piperidyl) propylamino]-4,6-dichloroacridone, from 1,4,6-trichloroacridone and 3-(Z-methyl-l-piperidyl)propylamine; 1 [4 (l-pyrrolidyl)butlyaminol- 4,6- diiodoacridone, from 1,4,6-triiodoacridone and 4- l-pyrrolidyl) butylamine; 1- [3- (2,5-dimcthyl- 1 pyrrolidyDpropylamino] 4,6 dichloroacridone, from 1,4,6-trichloroacridone and 3-(2,5-dimethyl-l-pyrrolidyl) propylamine; 1- [2- l-morpholinyl) ethylamino] -4,6-difluoroacridone, from 1,4,6-trifluoroacridone and 2-(4-morpholinyl)- ethylamine; 1 (2 diethylaminoethyla-mino)- 3 methyl 4,6 tricholoroacridone, from 1,4,6- trichloro-3-methylacridone and Z-diethylaminoethylamine; 1- [3- l-piperidyl) propylaminol -3- ethyl-4,6-dichloroacridone, from 1,4,6-trichloro- 3-ethylacridone and 3-(1-piperidyl) propylamine; 1 [2 (1 piperidyl) ethylamino] 3 n hexyl- 4,6-dibromoacridone, from 1,4,6-tribromo-3-nhexylacridone and 2-(1-piperidyl) ethylamine.

EXAMPLE 5 1- (3-diethylamino-Z-hydrorypropylamino) 4,6-dichloroacrid0ne A mixture of 20 g. of 1,4,6-trichloroacridone and 50 g. of 3-diethylamino-2-hydroxypropylamine was refluxed for two hours. The reaction mixture was made basic with sodium hydroxide solution and steam distilled. The residual mixture was cooled and the material that solidified was collected and taken up in dilute aqueous hydrochloric acid. The acidic solution was filtered and the filtrate made basic. The resulting solution was cooled, whereupon there separated a solid which was collected and recrystallized twice from dilute ethanol. This product was recrystallized two additional times from benzene-n-hexane,

thereby yielding as small orange prisms, 1-(3-diethylamino 2 hydroxypropylamino) 4,6 dichloroacridone, M. P. 160-162 C. (cor.).

Anal.Calcd. for CzoHzaClzNsOz; N, 10.29; 01, 17.37. Found: 151,10111; 01,1711.

alkyl or benzyl ester of an organic or inorganic acid. For example, its treatment, in ethanolic solution, with methyl iodide, ethyl sulfate; n-dodecyl chloride, benzy'l' chloride or ethyl paratoluenesulfonate results in the formation of 1 (3 diethylamino 2 hydroxypropylamino) 4,6-dichloroacridone methiodide, 1(3diethylamino 2 hydrox ropyiamino) 4,6 dich1oro= acridone ethosuli'ate, i-'(3-diethylamino-2-hydroxypropylamino)-4,6-dichloroacridone n-dodecochloride, 1-(3-diethylamino-2-hydroxypropylamino)-4,6-dichloroacridone benzochloride or 1 (3 diethylamino 2 hydroxyprop'ylarnino) 4,6-dichloroacridone etho-para-toluenesulfonate, respectively.

1 (3 diethylamino 2 hydroxypropylamino)-4,6-dichloroacridone in the form of an acid addition salt is obtained by treating the free base form with the appropriate acid. For example, treatment of an ethanolic solution of this aoridone with hydrogen chloride results in the formation of 1*(3-diethylamino-2-hydroxypropylamino) -4,6-dichloroacridone as its hydrochloride.

Other 1-(3-tertiary-amino-2-hydroxypropylamino)acridones, in the form of their free bases or addition salts, can be prepared according to the procedures given above, but using other l-haloacridones and 3 tertiary amino A 2 hy droxypropylamines in place of 1,4,6-trimethylacridone and 3-diethylamino-2-hydroxypropylamine, respectively. Thus, l-(3-di-n propylamino-2-hydroxypropylamino)-4-chloroacridone is obtained from lA-dichloroacridone and 3-di-npropylamino-2-hydroxypropylamine; 1- (3-diethylamino-2-hydroxypropylamino)acridone, from l-chloroacr-id'one and 3-diethylamino-2-hydroxy propylamine; 1-1 3- 1-piperidy1) 2-hydroxypropylaminol 3 n propyl 4 bromoacridone, from 1,4-dibromo-3-n-propy1acridone and 3-(1 piperidyl) -2-hydroxypropylamine; 1- [3- (Z-methyl 1 piperidyl) 2 hydro'xypr'opylaminol- 3,6-diethyl-4-cliloroacridcne, irom lA-dichloro- 3,6-diethylacridone and 3-(2-methyl-1-piperidyl) 2 hydroxypropylamine; 1 [3 (1 pyrrolidyl) 2 hydroxypropyla'minol 4. iodoacridone, from 1,4-diiodoacridone and 3-(1-pyrrolidyl) -2-hydroxypropylainine; 1- [3- (Z-methyl- 1 pyrrolidyl) 2 hydroxypropylamino] 3- chloro i methylacridone, from 1,3-dicholor0-4- methylacridone and 3-(2 methyl-1-pyrrolidyl)- 2-hydroxypropylamine; 1 [3- (4-morpholinyl) -2- hydroxypropylaminc) 3 chloro 4 methylfS-ethylacridone, from 1,3dichloro-4-methyl-6- ethylacridone and 3- (e-inorpholi'nyl) -2-hydroxypropylamine; 1- (3-diethylamino-2-hydroxypropylarnino) -3-bromo-6n-heXylacridone, from 1,3- dibromo 6 n hexylacridone and 3 diethyl-- amino-2-hydroxypropylamine; l- (3-diethylamino '-*2 hydro'xypropyiammoi 4 6 'd ibromo acridone, irom 1,4,6-tri bro'moacr and t di 10 ethylamino-2-hydroxypropylamine; 1- (B-diethylamino 2 hydroxypropylamino) 4,6 trichloro-3-methylacridone, from 1,4,6-tricholor-3- methyloacridone and 3-diethylamino-2-hydroxypropylamine.

' EXAMPLE 6 I-(Z-dz' n butyl'aminoethylamino) -4 methylacridone A mixture of 16 g. of 1chloro-4-methylacri-. done and 20 g. of 2-di-n-butylaminoethylaminewa refluxed gently for sixteen hours. The reaction mixture was poured onto ice and the solid that separated was collected. The solid was taken up in 100 ml. of acetic acid and the acidic solution diluted with about eight volumes of water. The resulting solution was filtered through a filter aid and the filtrate made basic; whereupon a-solid separated. The solid was recrystallized once from aqueous ethanol and once from ethanol, resulting in 5.0 g. of yellow crystalline 1- (2-di-n butylaminoethylamino) -4- methylacridone, M. P. 158.7-1.59.2 C. (c012) when 7 dried at C.

Anal.-Calcd. for Cz4HssN3O: C, 75.95; H, 8.76; N, 11.07. Found: C, 75.70; H, 8.52; N, 11.20.

When the above procedure is followedv but using l-chloro 3-methylacridone, 1 bromo-B- ethylacridone or l-chloroacridone in place-of lchloro-e-methylacridone, there is obtained 1-;(2- di-n-butylaminoethylamino) 3-methylacridone,

1-(:2-dienbutyla nino.ethylamino) 6-ethylacri-.-.. done or 1-(2-di-n butylaminoethylamino)acri-' done, respectively.

1-(2-di-n-butylaminoethylamino) 4 -meth'ylacridone in the form of its hydrochloride addi-' tion salt was obtained by suspending the yellow crystalline base form in hot absolute ethanol, adding ethanolic hydrogen chloride until the solution was acidic, adding absolute ether and triturating, while cooling, the gummy precipi tate with a glass rod until crystalline. The yellow crystals were collected and recrystallized from absolute ethanol, yielding l-(Z-di n-butylaminoethylamino)-4-methylacridone as its hydrochloride monohydrate, M. P. 19718-280 O. (cor.) when dried at 75 C. I

Anal.-Calcd. for CziHasNsoficll-lzozNg 9.68;

Cl. 8.17. Found: N, 9.77; CI, 8.24.

Other l-(tertiaryaminofalkylamino) -4-all ylacridones can be prepared according to the procedure given above but using other l-haloialkylacridones and te'rtiaiy-aminoalkylamines in place of l-chloro-4+methylacridone-and Z-di-n- 11 moacridone, from 1,6-dibromo-4-n-hexylacridone and 2 (4-morpholinyl) ethylamine.

EXAMPLE 7 A. 1,G-dichloro-4-methylacridone The intermediate 2- (2-methyl-5-chlorophenylamino)-4-chlorobenzoic acid was prepared following the procedure described above for Example 3A but using 103 g. of potassium 2,4-dichlorobenzoate, 70 g. of 2-methyl-5-chloroaniline, 270 ml. of n-amyl alcohol and 5 g. of copper powder. There was thus obtained 32 g. of product (recrystallized once from aqueous acetic acid) of sufllcient purity for use in the following cyclization reaction. A small sample was recrystallized a second time from acidic acid for analysis; M. P. 234-235" C.

Anal.-Calcd. Found: N, 4.08.

A mixture of 30 g. of 2-(2-methyl-5-chlorophenylaminmbenzoic acid and 220 ml. of concentrated sulfuric acid was heated at about 95 C. for four hours. The cooled reaction mixture was poured into ice water with stirring. The solid that separated was collected, suspended in dilute aqueous ammonium hydroxide solution and steam was passed through the resulting mixture for about thirty minutes. The remaining solid was collected and dried at 95 C. There was thus obtained 29 g. of 1,6-dichloro-4-methylacridone which was used without further purification in the reaction given below as Example 7B.

B. 1-(2-di-n-butylaminoethylamino) -4 methyl- 6-chloroacridone A mixture of 10 g. of 1,6-dichloro-4-methylacridone and 25 ml. of 2-di-n-butylaminoethylamine was heated at ZOO-210 C. for four hours. The reaction mixture was dissolved in ethanol and the ethanolic solution was treated with decolorizing charcoal, filtered and cooled. The resulting precipitate was recrystallized from ethanol, yielding 6.8 of yellow crystalline 1- (2-di-n butylaminoethylamino) 4-methyl-6- chloroacridone, M. P. 146.5-148.1 (con) when dried at 80 C.

Anal.-Calcd. fOl' C24H32C1N302 N, 10.15; Cl, 8.56. Found: N, 9.97; Cl, 8.79.

I claim:

1. An acridone having the structure I R4 where X is a member of the group consisting of CHzCHOHCHz and a lower alkylene radical having its two connecting linkages on different carbon atoms, N'RiRz is a member of the group consisting of lower dialkylamino, l-piperidyl, (lower alkylated) -1-piperidyl, l-pyrrolidyl, (lower alkylated) -i-pyrrolidyl and 4-morpholinyl, R3, R4 and R5 are each members of the group consisting of hydrogen, lower alkyl radicals and halo radicals.

2. A i-(dialkylaminoalkylamino) -4-haloacridone having the structure for C14H11C12NO2: N, 4.72.

(I? IfH-QI-N (lower alkyl): C

12 where X is a lower alkylene radical having its two connecting linkages on different carbon atoms,

and R4 is a halo radical.

3. A 1 (dialkylaminoalkylamino)-4,6-dihaloacridone having the structure where X is a lower alkylene radical having its two connecting linkages on different carbon atoms, and R4 and R5 are each halo radicals.

4. A l-(dialkylaminoalkylamino) -3-haloacridone having the structure where X is a lower alkylene radical having its two connecting linkages on different carbon atoms and R3 is a halo radical.

5. A l (dialkylaminoalkylamino) 4 alkyl fi-haloacridone having the structure (H) NHXN(lowcr alkyl);

II I c where R4 and R5 are each halo radicals.

7. A 1 (dialkylaminoalkylamino) 4 chloroacridone having the structure NH-X-N (lower alkyl where X is a lower alkylene radical having its two connecting linkages on different carbon atoms.

8. A 1-(dialkylaminoalkylamino) -4,6-dichloroacridone having the structure NHXN (lower alkyl);

where X is a lower alkylene radical having its two connecting linkages on difierent carbon atoms.

13 9. A 1 (dialkylaminoalkylamino) 3 chloroacridone having the structure (H) l IIHXN (lower alkyl); o

where X is a lower alkylene radical having its two connecting linkages on difierent carbon atoms.

10. A l-(dialkylaminoalkylamino) -4-methy1- 6-chloroacridone having the structure (1) NHX-N(lower alkyl A (SH,

where X is a lower alkylene radical having its two connecting linkages on different carbon atoms.

11. A 1 (3 dialkylamino 2 hydroxypropylamino) 4,6 dichloroacridone having the structure J CI OiN 12. The process of preparing an acridone having the structure NHCHaOHOHCHaNUOWGr alkyl):

Hill

0 halogen C Ra[IN Q Ri with a diamine having the formula R1R2N-X-NH2 13. A process according to claim 12 where X is a lower alkylene radical having its two connecting linkages on different carbon atoms, R1 and R2 are each lower alkyl radicals, R4 is a halo radical, and R3 and R5 are each H.

14. A process according to claim 12 where X is a lower alkylene radical having its two connecting linkages on different carbon atoms, R1 and R1 are each lower alkyl radicals, R3 is H, and R4 and R5 are each halo radicals.

15. A process according to claim 12 where X is a lower alkylene radical having its two connecting linkages on difierent carbon atoms, R1 and R2 are each lower alkyl radicals, R3 is a halo radical, and R4 and R5 are each H.

16. A process according to claim 12 where X is a lower alkylene radical having its two connecting linkages on different carbon atoms, R1 and R2 are each lower alkyl radicals, R3 is R, R4 is a lower alkyl radical and R5 is a halo radical.

17. A process according to claim 12 where X is CH2CHO-HCH2, R1 and R2 are each lower alkyl radicals, R3 is H, and R1 and R5 are each halo radicals.

18. 1 (3 diethylaminopropylamino) 4- chloroacridone.

19. 1 (3 diethylaminopropylamino) 4,6- dichloroacridone.

20. 1 (3 diethylaminopropylamino) 3- chloroacridone.

21. 1 (2 di n butylaminoethylamino)- 4 methyl 6 chloroacridone.

22. l (3 diethylamino 2 hydroxypropylamino) 4,6 dichloroacridone.

SYDNEY ARCHER.

No references cited. 

1. AN ACRIDONE HAVING THE STRUCTURE 